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Junctional adhesion molecule-A is co-expressed with HER2 in breast tumors and acts as a novel regulator of HER2 protein degradation and signaling

Oncogene volume 32, pages 2799–2804 (2013)Cite this article

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Abstract

Junctional adhesion molecule-A (JAM-A) is a membranous cell–cell adhesion protein involved in tight-junction formation in epithelial and endothelial cells. Its overexpression in breast tumors has recently been linked with increased risk of metastasis. We sought to identify if JAM-A overexpression was associated with specific subtypes of breast cancer as defined by the expression of human epidermal growth factor receptor-2 (HER2), estrogen receptor (ER) and progesterone receptor. To this end, JAM-A immunohistochemistry was performed in two breast cancer tissue microarrays. In parallel, cross-talk between JAM-A, HER2 and ER was examined in several breast cell lines, using complementary genetic and pharmacological approaches. High JAM-A expression correlated significantly with HER2 protein expression, ER negativity, lower patient age, high-grade breast cancers, and aggressive luminal B, HER2 and basal subtypes of breast cancer. JAM-A and HER2 were co-expressed at high levels in vitro in SKBR3, UACC-812, UACC-893 and MCF7-HER2 cells. Knockdown or functional antagonism of HER2 did not alter JAM-A expression in any cell line tested. Interestingly, however, JAM-A knockdown decreased HER2 and ER-α expression, resulting in reduced levels of phospho-(active) AKT without an effect on the extracellular signal-related kinase phosphorylation. The downstream effects of JAM-A knockdown on HER2 and phospho-AKT were partially reversed upon treatment with the proteasomal inhibitor MG132. We conclude that JAM-A is co-expressed with HER2 and associates with aggressive breast cancer phenotypes. Furthermore, we speculate that JAM-A may regulate HER2 proteasomal degradation and activity, potentially offering a promise as a therapeutic target in HER2-positive breast cancers.

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Abbreviations

HER2:

human epidermal growth factor receptor-2

JAM-A:

junctional adhesion molecule-A.

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Acknowledgements

We are grateful for funding from Science Foundation Ireland (2008/RFP/NSC1427 to AMH), to Dr Tony O'Grady and Trudi Roche for their assistance with obtaining tissue microarray clinical data, and to Dr Marie McIlroy for statistical advice. Herceptin was a kind gift from the St James' Hospital Pharmacy, Dublin, Ireland; LCC1 cells were a kind gift from Professor Robert Clarke, Georgetown University, USA; and MCF7-HER2 cells were a kind gift from Professor Dennis Slamon, University College Los Angeles, USA and Dr Norma O'Donovan, Dublin City University, Ireland.

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  1. E A McSherry

    Present address: 3Current address: Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada.,

Authors and Affiliations

  1. Department of Surgery, RCSI Education and Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland

    K Brennan, E A McSherry, L Hudson, A D K Hill, L S Young & A M Hopkins

  2. Department of Pathology, RCSI Education and Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland

    E W Kay

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Correspondence to A M Hopkins.

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Brennan, K., McSherry, E., Hudson, L. et al. Junctional adhesion molecule-A is co-expressed with HER2 in breast tumors and acts as a novel regulator of HER2 protein degradation and signaling. Oncogene 32, 2799–2804 (2013). https://doi.org/10.1038/onc.2012.276

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